Michael D. Hughson

Breast cancer (BC) consists of several subtypes that vary regionally by incidence and mortality rates. The study population consisted of 1411 incident BCs diagnosed in Sulaimania, Iraq, in the years 2009-2014. Based upon positive (p) or negative (n) reactions, hormone receptor (HR)pHER2n tumors were divided into low recurrence risk (HRp low-risk) and high recurrence risk (HRp high-risk) subtypes with the Magee 2 equation that uses pathological data, without a Ki67 index. The 5-, 10-, and 13-year distant disease-free survival (DDFS) rates for the subtypes were estimated using proportional hazards models. The median age of patients for all subtypes was < 50 years. The proportion of subtypes was 29.6% for HRp low-risk, 36.2% for HRp high-risk, 11.8% for HRpHER2p, 11.7% for HRnHERp, and 10.6% for triple-negative (TN) BC. The 5-, 10-, and 13-year DDFS rates were as follows: HRp low-risk (n = 418, 85.5%, 74.4%, 71.7%), HRp high-risk (n = 511, 76.2%, 62.8%, 58.7%), HRpHER2p (n = 167; 77.7%, 58.6%, not reached), HRnHER2p (n = 165; 60.4%, 46.6%, not reached), and TNBC (n = 150; 61.4%, 54.2%, not reached). The difference in DDFS between HRp low-risk vs HRp high-risk was significant, p < 0.001, as were the differences between HRp high-risk vs HRnHER2p and HRp high-risk vs TNBC, both p < 0.001. The difference in DDFS between HRp high-risk vs HRpHER2p BC was not significant, p = 0.83, nor was the difference between HRnHER2p vs TNBC, p = 0.91. Distant disease or death from breast cancer was identified for 395 patients, 86 with HRp low-risk, 137 with HRp high-risk, 50 with HRpHERp, 69 with HRnHER2p, and 53 with TNBC. Iraqi HRpHER2n BCs can be separated into low and high risk using the Magee 2 risk assessment equation. The HRp low-risk BC has a favorable outcome. HRp high-risk was the most common subtype and the major cause of recurrent distant disease.

Arterionephrosclerosis is characterized by focal global glomerulosclerosis (FGGS), which is a constant feature of aging and hypertension. FGGS begins as normal‐appearing glomeruli that undergo tuft contraction (TC) and progress to global glomerulosclerosis (GGS). Kidney tissue from 26 hypertensive and 25 age‐matched non‐hypertensive patients was analyzed for glomerular volume and for podocyte number using a WT1 antibody. Immunohistochemistry (IHC) was employed to detect the senescence‐related biomarkers p16, p21, β‐galactosidase (GLB1), and 5‐nucleotidase (CD73). Antibodies against annexin 3 (ANXA3), cytokeratin 7, and CD44 were used to evaluate parietal epithelial cell (PEC) activation. The relationships between biomarkers, hypertension, TC, and GGS were quantitatively analyzed. With TC, podocyte numbers decreased in association with increased glomerular p16, p21, GLB1, and CD73 expression. With TC, WT1, CK7, and CD44‐expressing PEC increased. TC and GGS expressed senescent markers in hypertensive and non‐hypertensive kidneys; however, the frequency of TC ( p < 0.01) and GGS ( p < 0.001) was greater in hypertensive kidneys, and glomerular expression of senescence markers was correspondingly higher. Additionally, greater p16 and p21 expression was observed in the tubular atrophy of hypertension. As FGGS developed, podocyte depletion, cellular senescence markers, and PEC activation were associated with TC and increased with hypertension.

Melanin deposition in the kidney is rare and appears limited to the conditions of oculocutaneous albinism and malignant melanoma with melanuria. Melanin is generally an insoluble polymer, and it is curious how people with albinism who have little or no skin pigmentation can secrete melanin into the bloodstream, have it pass through the glomerular filtration barrier, and be absorbed by renal tubules. The concentration and solubility of melanin were analyzed in kidney tissue and urine of a renal transplant donor who had a pre-nephrectomy biopsy performed on a black kidney. Genetic testing of a donor blood sample found a novel homozygous Hermansky-Pudlak syndrome (HPS) HPS1 mutation (c.70G > T; p.Glu24Ter). Melanin was extracted from a 24-hour urine collection, and tissue and urine melanin concentrations were determined by spectrophotometry. In the kidney, non-melanosomal melanin was deposited as granules in the proximal tubular epithelium and as large aggregates within macrophages in renal tubular lumens. The kidney melanin concentration was 2 mg/g of tissue. Urine melanin was mainly water-soluble, with an excretion of eumelanin that is within a reported normal range. Water-soluble melanin was excreted in the urine of a kidney donor with a novel HSP1 mutation predicted to produce a truncated protein. This resulted in melanin pigmentation of a kidney transplanted into a normally pigmented sibling. Donor and recipient are healthy 3 years after the transplant. Nevertheless, HSP can be associated with kidney, colon, and lung pathology, and the long-term outlook for the recipient kidney and donor’s health is uncertain.

Burkitt's lymphoma (BL) has worldwide variations in incidence that are related to the age of Epstein-Barr virus (EBV) infection. This study examined the age-specific incidence rate (ASIR) of BL and community EBV seropositivity in Iraqi Kurdistan and compared results with data from countries tabulated in the International Incidence of Childhood Cancer volume 3 (IICC-3). The ASIR (95% confidence intervals) of BL in Sulaimani Governorate of Iraqi Kurdistan were calculated for the years 2010–2020. Specimens from 515 outpatients were tested for IgG and IgM antibodies to EBV viral capsid antigen. In Sulaimani, 84% of BL occurred under 20 years of age, with an ASIR of 6.2 (4.7–7.7) per million children. This ASIR was not significantly different than that of Egypt, Morocco, Israel, Spain, or France. It was slightly higher than the ASIR of the United States, the United Kingdom, and Germany and markedly higher than for Asia and South Africa. In Africa and much of Asia, early childhood EBV exposure predominates, with nearly all children being infected by 5 years of age. In Sulaimani, just over 50% of children were EBV seropositive at 3 years old and 90% seropositivity was reached at 15 years of age. In Europe and North America, seropositivity is commonly delayed until adolescence or young adulthood and adult predominates over childhood BL. In the Middle East, childhood BL is relatively common and adult BL is rare. In Sulaimani, EBV seropositivity increases progressively throughout childhood and reaches 92% at mid-adolescence. This may reflect the Mid East more widely. We suggest that the high childhood and low adult BL rates may be a regional effect of a pattern of EBV exposure intermediate between early childhood and adolescent and young adult infections.

Background Burkitt's lymphoma (BL) is rare, with variations in regional incidence related with the age of Epstein-Barr virus (EBV) infection. This study examined the age-specific incidence rate (ASIR) of BL and the age of community EBV infection in Northern Iraq and other countries tabulated in the WHO IICC-3. Materials and Methods The ASIR and 95% confidence interval (95%CI) of BL in Sulaimani Governorate were calculated for the years 2010—2020. Tumor EBV latency was determined by in situ hybridization for EBV-encoded mRNA (EBER). Specimens from 515 outpatients were tested for IgG antibodies to EBV viral capsid antigen (VCA). Results In the Middle East, BL is predominantly a pediatric tumor, with an ASIR in Sulaimani of 6.2 (4.7–7.7) per million children. This ASIR is not significantly different than that of Egypt, Morocco, Israel, Spain, and France. It is slightly higher than the ASIR of the United States, the United Kingdom, and Germany and markedly higher than for Asia and South Africa. In Africa and much of Asia, EBV is acquired in early childhood. In Sulaimani, EBV seropositivity develops in late childhood and early adolescence. In Europe and North America, seropositivity is acquired in adolescents and young adults (AYD). In countries with AYD infections, adult predominates over childhood BL. Conclusions Early childhood EBV infections associate with low rates of childhood BL and few adult BL. In the Middle East, childhood BL is relatively common while adult BL is rare. In our region, half of EBV infections is found in late childhood. This may reflect the Mid East more widely. The high childhood/low adult BL rates may be a regional influence of EBV exposure intermediate between early childhood and AYD infections.

In the developing world, transplantation is the most common long-term treatment for patients with end-stage renal disease, but rates and causes of graft failure are uncertain. This was a retrospective outcomes study of renal transplant patients seen in Iraqi Kurdistan nephrology clinics in the year 2019. In 2019, 871 renal transplant patients were registered and outcomes followed through 12/31/2020. Indicated renal biopsies were obtained on 431 patients at 1 day to 18 years post-transplantation. Outcomes were compared with United States Renal Data System (USRDS) living donor reports. All donors were living. The recipient age was 38.5 ± 13.3 years, 98.2% were < 65 years old, 3.7% had previous transplants, and 2.8% had pretransplant donor-specific antibodies (DSA). Gehan-Breslow estimated failure rates for all-cause, return to HD, and death with functional graft were 6.0, 4.2, and 1.9% at 1 year and 18.1, 13.7, and 5.1% at 5 years post-engraftment (USRDS 2000; 1 year: 7.0, 5.0, 2.6%; 5 year: 22.3, 15.2, 10.6%. USRDS 2010; 1 year: 3.7, 2.4, 1.4%; 5 year: 15.3, 9.6, 7.3%). The median graft survival was 15 years. Acute tubular injury (ATI), infarction, and acute T cell-mediated rejection accounted for 22.2% of graft loss, with > 75% of these failures taking place in the first year. Most graft failures occurred late, at a median post-transplant time of 1125 (interquartile range, 365–2555) days, and consisted of interstitial fibrosis and tubular atrophy (IF/TA) (23.8%), transplant glomerulopathy (13.7%), and acquired active antibody-mediated rejection (12.0%). The significant predictors of graft loss were C4d + biopsies (P < 0.01) and advanced IF/TA (P < 0.001). Kurdistan transplant patients had graft failure rates similar to living donors reported by the USRDS for the year 2000 but higher than reported for 2010. Compared to USRDS 2010, Kurdistan patients had a moderate excess of HD failures at one and 5 years post-engraftment. Nevertheless, prolonged survival is the norm, with chronic disorders and acquired DSA being the leading causes of graft loss.

Background In the developing world, transplantation is the most common long-term treatment for patients with end-stage renal disease, but rates and causes of graft failure are uncertain. Methods In 2019, in Iraqi Kurdistan, 301 of 871 renal transplant patients had indicated graft biopsies. Outcomes were followed over the subsequent year of 2020. Results The post-transplantation time ranged from one day to 18 years. All donors were living. Approximately 15% of transplants were preemptive. Pretransplant hemodialysis (HD) was twice weekly and less than one year. The median recipient age was 39 (IQR 28 to 48) years. 5.5% of recipients had previous transplants; 3.7% had pretransplant donor-specific antibodies (DSA). The Kaplan-Meier estimated graft failure rates for all-cause, return to HD, and death with functional graft (DWFG) were 9.1%, 6.3%, and 2.9% at one year and 23.8%, 6.3%, and 7.4% at five years. The median death-censored graft survival was 15 years. The most frequent biopsy diagnoses associated with graft failure were interstitial fibrosis and tubular atrophy (IF/TA) (23.1%), transplant glomerulopathy (13.7%), and acquired active antibody-mediated rejection (11.1%). The significant predictors of graft loss were C4d + biopsies (P < 0.01) and advanced IF/TA (P < 0.001). Conclusions These Iraqi patients had estimated graft failure rates similar to the United States (US) Renal Data System living-donor outcomes reported for the year 2000. The inability to approach recent US graft survivals may owe to inadequate pretransplant dialysis. Nevertheless, prolonged survival made chronic disorders and acquired DSA the leading causes of graft failure and is creating a need for second transplants.

Background: The incidence of kidney diseases among bodybuilders is unknown. Methods: Between January 2011 and December 2019, the Iraqi Kurdistan 15 to 39 year old male population averaged 1,100,000 with approximately 56,000 total participants and 25,000 regular participants (those training more than one year). Annual age specific incidence rates (ASIR) with (95% confidence intervals) per 100,000 bodybuilders were compared with the general age-matched male population. Results: Fifteen male participants had kidney biopsies. Among regular participants, diagnoses were: focal segmental glomerulosclerosis (FSGS), 2; membranous glomerulonephritis (MGN), 2; post-infectious glomeruonephritis (PIGN), 1; tubulointerstitial nephritis (TIN), 1; and nephrocalcinosis , 2. Acute tubular necrosis (ATN) was diagnosed in 5 regular participants and 2 participants training less than one year. Among regular participants, anabolic steroid use was self-reported in 26% and veterinary grade vitamin D injections in 2.6%. ASIR for FSGS, MGN, PIGN, and TIN among regular participants was not statistically different than the general population. ASIR of FSGS adjusted for anabolic steroid use was 3.4 (-1.3 to 8.1), a rate overlapping with FSGS in the general population at 2.0 (1.2 to 2.8). ATN presented as exertional muscle injury with myoglobinuria among new participants. Nevertheless, ASIR for ATN among total participants at 1.4 (0.4 to 2.4) was not significantly different than for the general population at 0.3 (0.1 to 0.5). Nephrocalcinosis was only diagnosed among bodybuilders at a 9-year cumulative rate of one per 314 vitamin D injectors. Conclusions: Kidney disease rates among bodybuilders were not significantly different than for the general population, except for nephrocalcinosis that was caused by injections of veterinary grade vitamin D compounds.

Background: The incidence of kidney diseases among bodybuilders is unknown. Methods: Between January 2011 and December 2019, the Iraqi Kurdistan 15 to 39 year old male population averaged 1,100,000 with approximately 56,000 total participants and 25,000 regular participants (those training more than one year). Annual age specific incidence rates (ASIR) with (95% confidence intervals) per 100,000 bodybuilders were compared with the general age-matched male population. Results: Fifteen male participants had kidney biopsies. Among regular participants, diagnoses were: focal segmental glomerulosclerosis (FSGS), 2; membranous glomerulonephritis (MGN), 2; post-infectious glomeruonephritis (PIGN), 1; tubulointerstitial nephritis (TIN), 1; and nephrocalcinosis , 2. Acute tubular necrosis (ATN) was diagnosed in 5 regular participants and 2 participants training less than one year. Among regular participants, anabolic steroid use was self-reported in 26% and veterinary grade vitamin D injections in 2.6%. ASIR for FSGS, MGN, PIGN, and TIN among regular participants was not statistically different than the general population. ASIR of FSGS adjusted for anabolic steroid use was 3.4 (-1.3 to 8.1), a rate overlapping with FSGS in the general population at 2.0 (1.2 to 2.8). ATN presented as exertional muscle injury with myoglobinuria among new participants. Nevertheless, ASIR for ATN among total participants at 1.4 (0.4 to 2.4) was not significantly different than for the general population at 0.3 (0.1 to 0.5). Nephrocalcinosis was only diagnosed among bodybuilders at a 9-year cumulative rate of one per 314 vitamin D injectors. Conclusions: Kidney disease rates among bodybuilders were not significantly different than for the general population, except for nephrocalcinosis that was caused by injections of veterinary grade vitamin D compounds.